Little is known about how forebrain structures modify pain in the spinal cord dorsal horn, and whether such modulation is influenced by conditions such as sex of the subject, or the type of pain (nociceptive versus neuropathic). Using female rats, we have shown that stimulating the lateral hypothalamus (LH) in a thermal nociception model produces opposing modulation in the spinal cord dorsal horn, whereby alpha2- adrenoceptors mediate antinociception, while alpha1-adrenoceptors mediate opposing, concurrent pronociception. Antinociception predominates, but is attenuated by the pronociceptive effect. Our pilot data show that LH stimulation also produces antinociception in male rats in the thermal nociceptive model (n = 6) and in both males (n = 6) and females (n = 11) in a model of neuropathic pain (the chronic constriction injury model, or CCI). Therefore, the aim of this competing continuation proposal is to extend our findings to the CCI model and to examine sex differences in both the thermal nociception and CCI models via LH stimulation of the alpha-adrenoceptor-mediated opposing response in the spinal cord dorsal horn. In two experiments, the LH will be stimulated with carbachol in different doses (125, 250, and 500 nmol plus 62 nmol control) alone and with intrathecal injection (IT) of alpha-adrenoceptor antagonists. We will then examine the effect of sex and pain model on the mechanisms of the alpha-mediated opposing response as measured by the tail flick (TFL) and foot withdrawal latency (FWL). In all experiments, we will take blood samples to measure serum estrogen and progesterone to establish the hormonal milieu of females at the time of the experiment. Using multivariate statistical analysis, we will determine whether LH stimulation at three different carbachol doses produces different responses in alpha-adrenoceptor subtype-mediated nociceptive modulation in the thermal nociceptive and CCI models, and whether female responses differ from males. The benefits of this study come from understanding the neural mechanisms involved in endogenous analgesia that can lead to the development of more effective clinical treatments that reduce pain and promote analgesia for females as well as males. PUBLIC HEALT RELEVANCE: The proposed study will examine how one brain structure (lateral hypothalamus) prevents recognition of two forms of pain in male and female rats. The two forms of pain are acute pain caused by tissue injury and neuropathic pain from damage to nerves. We hypothesize that the lateral hypothalamus will decrease the recognition of both types of pain in female rats more than male rats.